O-(beta-hydroxyethyl)-hydroxylamines and process for their manufacture



United States Patent 3,344,190 0-(B-HYDROXYETHYL)-HYDROXYLA1\IINES ANDPROCESS FOR THEIR MANUFACTURE Bruno J. R. Nicoiaus, Milan, Italy, andEmilio Testa, Vacallo Tessin, Switzerland, assignors to Lepetit S.p.A.,Milan, Italy No Drawing. (Driginal application Feb. 21, 1962, Ser. No.174,671, now Patent No. 3,184,500, dated May 18, 1965. Divided and thisapplication Sept. 21, 1964, Ser. No. 398,103

Claims priority, application Great Britain, Feb. 22, 1961,

6,498/ 61 9 Claims. (Cl. 260-584) The present invention relates tosubstituted hydroxylamines and to a method for their manufacture.

This application is a division of our copending application, Serial No.174,671, filed February 21, 1962 now Patent No. 3,184,500.

The compounds of this invention are of the general formula HOCH CH ONRwherein R is hydrogen or a lower alkyl radical. These compounds areuseful particularly as intermediates for the manufacture ofpharmaceutical preparations, such as compounds of the formula whereinAcyl represents a lower alkanoyl or a benzoyl, phenylacetyl,diphenylacetyl, phenylcarbamyl, cinnamoyl or succinyl radical, R is alower alkyl radical, and their quaternary salts with lower alkylhalogenides. These compounds are highly active in pharmacological testson animals. For instance, O-(/8-acetoxyethyl)-N,N-dimethy1 hydroxylaminemethiodide and the fl-succinyl analogue of the same, as well as thecorresponding N,N-di-lower alkyl homologues in which the alkyl is ethyl,propyl or butyl, are nearly as active as acetylcholine andsuccinylcholine and the well known quaternary addition salts of the sameas curare-like agents. O-(fl-diphenylacetoxyethyl)-N,N- dimethylhydroxylamine hydrochloride shows a strong analgesic and sedativeaction. O-([3-phenylcarbamyloxyethyl)-N,N-dimethyl hydroxylamine has amarked tranquillizing effect. These main activities are more or lessshared by a large majority of the compounds of the class.

The process for preparing the compounds of this invention and theirconversion to the esters claimed in the above-identified parentapplication may be represented as follows:

The starting 0 carbethoxymethyl N carbethoxyhydroxylamine ishydrogenated with lithium aluminium hydride in an inert anhydrousorganic solvent at a temperature not exceeding 0 C. This provision isnecessary to avoid evolution of ammonia and carbon dioxide withformation of ethylene glycol. The obtainedO-(B-hyd-roxyethyl)-N-carbethoxy-hydroxylamine (II) is refluxed with anaqueous solution of a strong mineral acid, such as hydrochloric acid,giving the key intermediate O-(/3- hydroxyethyl)-hydroxylamine (III).This is N-alkylated by conventional processes to yield the N, N-dialkylderivative IV. For this purpose, when the dimethyl derivative isdesired, III can be conveniently reacted with a mixture of formic acidand formaldehyde. In all other cases, i.e., when R of the generalformula is a lower alkyl other than methyl, III is reacted with theappropriate alkyl halogenide, such as ethyl or butyl bromide. The O-acylation of IV is also performed by conventionally acylation proceses,as f.i., by employing the appropriate acyl halide or anhydride.

The last steps of the process, though old in the art, in

connection with other compounds, are however to be considered as novelin our processes in the sense that the physical-and chemical propertiesof O-(fi-hydroxyethyD- hydroxylamine were entirely unknown at the datesof our parent application. No information was available about thestability of the N() linkage, and quite different results could beexpected by subjecting the key intermediate III to such vigorousreactions as refluxing with alkyl halogenides or heating with acarboxylic acid anhydride. The achieved results are therefore to beconsidered as an extremely useful tool for further study in the field oforganic medicinal chemistry.

The following examples are illustrative of the invention.

EXAMPLE 1 0- (fl-propz'onoxyethyl) -N,N-dimethyl-hydroxylamine To 71 g.lithium aluminum hydride in 4000* ml. anhydrous ethyl ether 237 g. ofO-carbethoxymethyl-N- carbethoxy-hydroxylamine dissolved in 1000 ml.ethyl ether are added under stirring at 0 C. Stirring is continued for 5hours; then solid CO in small pieces and H 0 (150 ml.) are added over aperiod of 1.5 hours. The mixture is filtered, the inorganic compoundswashed with ethyl ether, the ether solution dried over Na SO andconcentrated in vacuo; an oil is obtained which is distilled through afractionating column. Yield 46% of N-carbethoxyO-(fi-hydroxyethyl)-hydroxylamine; B.P. 1212'- /0.8 mm.

A mixture of 19.8 g. of -N-carbethoxy-O-(fi-hydroxyethyl)-hydroxylamineand 100 ml. 15% HCl is refluxed for 1 and /2 hours. The clear solutionis concentrated in vacuo on a water bath; the oily residue is taken upwith ml. anhydrous methyl alcohol and the solution neutralized withalcoholic KOH. The inorganic salt is filtered off, and the solutionconcentrated in vacuo. An oil is obtained, which distilled through afractionating column gives O-(fi-hydroxyethyl)-hydroxylamine. B.P.6162/1 mm. Yield 74.11%.

Into 146.5 g. 90% formic acid cooled with ice-water, 41 g.O-(B-hydroxyethyl)-hydroxylamine and 107.5 g. 30.1% formaldehyde areadded dropwise under stirring, then the mixture is refluxed 3 /2 'hours.The obtained solution is cooled to 0 and under stirring 69.2 g.concentrated H01 are added. By concentrating in vacuo an oil is obtainedwhich is dissolved in 250-300 ml. CH OH. Sodium methoxide in methylalcohol is added to adjust the pH to 8-410, the inorganic salt isfiltered off and the solution concentrated in vacuo. The oily residue isrectified with a fractionating column. Yield 36.6% of O-(flhydroxyethyl-N-dimethyl-hydroxylamine.

To a mixture of 4 g. of O-(B-hydroxyethyl) -N-dimethylhydroxylamine in25 ml. of tetrahydrofuran and 3.85 g. of triethylamine kept at 0, 3.52g. of propionyl chloride in 15 ml. of tetrahydrofuran are added. Themixture is refluxed for 1 /2 hours. After filtration of the precipitatedsalt, the solution is concentrated in vacuo and the oily residue isrectified with a fractionating column. Yield 45%, B.P. 7883/45 mm. Hg.

3 EXAMPLES 2-4 The following derivatives are prepared by an analogousprocedure to that described in Example 1; R and acyl are, located as inthe generic formula above:

4 amine, 174 g. of ethyl iodide, 93.6 g. of sodium bicarbonate and 400'ml. of anhydrous ethanol is refluxed for 8 hours and allowed to standovernight at room temperature. After filtration the solution isevaporated to dryness.

R Acyl B.P. Yield, percent Dirnethyl(CH hNOCHzCHzOCOCHa Aeetylss-s9/4smm.H 73 Dimethyl (CII3)2NOCH2OH2OCOC6H5 Benzoyl--. 103-s12 mm.Hg 39 Dimelihyl GH3)2NOCHzGHzOCOCHzCaIIs Pheuylacetyl- 95-97/0.5mm.Hg 6:

EXAMPLE The residue is distilled in vacuo, collecting at 4849/ 1.2 mm.Hg. Yield 34 g. of O-(B-acetoxyethyl)-N,N-diethyl- 0 (B xxg gz gghydmxylamme hydroxylamine, B.P. 73 C. The methiodide is prepared throughconventional procedures and has M.P. 62-65 C.

A mixture of 9.6 g. O-(fl-hydroxyethyl)-N,N-dimethylhyd-roxylamineacetate in 50 ml. anhydrous ethyl ether, EXAMPLES 10-11 48 g. 01-1 1 and3 ml. anhydrous methyl alcohol is stirred By the same procedures asdescribed in the preceding for 10 minutes. After standing 48 hours a.yellow examples the following compounds were prepared: precipitateforms. Yield 57% M.P. 9295.O-(fi-hydroxyethyl)-N,N-dipropylhydroxylamine, B.P.

EXAMPLE 6 O-(B-acetoxyethyl)-N,N-dipropylhydroxylamine, B.P. -(fiy y yxy i 60-65/0.6 m. Hg. The methiodide has M.P. 86-89 C. To a mixture of2.5 g.O-(flhydroxyethyl)-N-dimethylo'(ofihydroxyethyl)NNdibutylhydroxylamine,

hydroxylamine, 25 ml. anhydrous ethyl ether and 2.4 g. 7748triethylamine, cooled at 0", 3.96 g. cinnamoyl chloride in Oacetoxyethyl)NN"fflbl{tylhydmxylammei 1 15 ml. anhydrous ethyl ether areadded under stirring. 74-76 The methlodlde has The mixture is refluxedfor 2 hours, filtered and washed claim: with ethyl ether. The ethersolution is washed with a An -(fiy Xyethyl)-hydroxylam1ne of thesaturated solution of NaHCO then with 10% HCl and formula: I water,dried over Na SO and concentrated in vacuo. The HOCH2CH2ON(R )2 Obtain dOil iS dist d i V Yield 1339- wherein R is a member of the groupconsisting of hydrol2l-l23/0.5 mm. Hg. gen and lower alkyl.

EXAMPLE 7 f2.h Afn O-1(B-hydroxyethyl)-N,N-dialkylhydroxylamine o t eormu a O-( fi-dlpheny lacetoxyethy -N,N- dzmefhy Z- HOCHZCH2ON(R) 2hydioxylamme hydrochloride 40 wherein R 18 a lower alkyl radical.

To a mixture of 2.1 g. O-(B-hydroxyethyl)-N-(d1- O (5 hydmXyethy1)hydmxylamine methyD-hydroxylarrnne, 21 ml. of anhydrous ethyl ether 4' o.(fi hydroxyethyl) NN dimfithylhydmxylamine. and 2.1 g. of tnethylamme,a solution of 4.6 g. of 5' o ,(fi hydmxyethyn N,N dipropylhydmxylamine.a,oc-d1phenylacetylchloride m 15 ml. of diethyl ether 1s o (fihydroxyethyl)iNNdiblHy}hydroxylamine added dropwlse under stirring,keeping the temperature at 5 A process for preparing o (fi hydmxyethyl)0. Stirrmg 1s contmued 1 hour, thenthe mixture is hydroxylamine whichcomprisas hydrogenating Ocap {fifluxfld for 1 hour- After Standmg Vermght the Imxmre bethoxymethyl-N-carbethoxy-hydroxylamine with lithiumfiltered: the Solvent {emoved and the ollyfesldue crystal aluminiumhydride in an inert anhydrous organic solvent lized fror n anhydrousisopropyl alcohol. Yield 60%, MP. at a temperatum below 0 C andrefluxing the obtained 105-110 E PLE 8O-(B-hydroxyethyl)-N-carbethoXy-hydroxylarnine with an XAM aqueoussolution of a strong mineral acid. O-(fi-phenylcarbamyloxyethyl)-N,N-dih l. 8. prtlicess as in claim 7, wherein the inert anhydroushydroxylamine organic so vent is anhydrous ethyl ether.

9. A process as in claim 7 wherein the strong mineral A mixture of 14.1g. O-(B-hydroxyethyl)-N,N-d1- methyl-hydroxylamine and 17.6 g. ofphenylisocyanate is acid 15 aqueous hydrochlonc acid stirred at roomtemperature and then warmed on a water R f d bath at 50-55 for 1 hour. Awhite solid precipitates, e Memes l e which is collected andcrystallized from light petroleum. UNITED STATES PATENTS Yield 77%, MP.62-64. 3,184,500 5/1965 Nicolaus et al. 260-469 EXAMPLE 9O-(pl-aCetOxyethyZ) -N,N-diethylhydroxylwmine A mixture of 40 g. ofO-(B-hydroxyethyl-hydroxyl- CHARLES B. PARKER, Primary Examiner.

D. R. PHILLIPS, Assistant Examiner.

1. AN O-(B-HYDROXEYETHYL)-HYDROXYLAMINE OF THE FORMULA:
 7. A PROCESS FORPREPARING O-(B-HYDROXYETHYL)HYDROXYLAMINE, WHICH COMPRISES HYDROGENATINGO-CARBETHOXYMETHYL-N-CARBETHOXY-HYDROXYLAMINE WITH LITHIUM ALUMINIUMHYDRIDE IN AN INERT ANHYDROUS ORGANIC SOLVENT AT A TEMPERATURE BELOW0*C. AND REFLUXING THE OBTAINEDO-(B-HYDROXYETHYL)-N-CARBETHOXY-HYDROXYALAMINE WITH AN AQUEOUS SOLUTIONOF A STRONG MINERAL ACID.